This project will define the mechanism by which equol, an isoflavone metabolite, acts to inhibit normal and pathological growth of the prostate gland. In the United States, prostate cancer is the most frequently diagnosed cancer in men, and ranks second among cancer-related male deaths. The development of prostate cancer involves a complex interplay of numerous factors, however lifetime exposure to androgens, and advancing age, are two necessary etiological factors. Similarly, the development of benign prostatic hypertrophy (BPH) is also dependent upon androgen exposure and it is estimated that over half of the male population in the United States over the age of 60 have symptoms of BPH. The importance of androgen in prostate gland pathology is evidenced by current therapies for these diseases, which include reduction in circulating testosterone;inhibition of 5-alpha reductase, an enzyme that synthesizes the potent androgen, dihydrotestosterone;or blocking the actions of the androgen receptor. Diet is an important consideration when examining risk factors for hormone-dependent diseases such as prostate cancer. Asian men, on an eastern diet, have the lowest incidence of prostate cancer in the world. The basis for this correlation may be the presence of estrogen-like isoflavones (genistein and daidzein), in their diet. We have recently shown that equol, a product of isoflavone metabolism, has anti- androgenic properties as well. Equol selectively binds dihydrotestostserone and prevents androgen receptor activation to reduce androgen-dependent prostate growth. Equol is the principal metabolite of daidzein. It circulates at high levels, and is concentrated in the prostate. Moreover, equol can selectively bind estrogen receptor beta to activate an anti-proliferative cascade in prostate. Thus, equol possesses a unique dual action to inhibit prostate growth by 1) preventing proliferative actions of androgens, and 2) activating anti-proliferative actions of ERbeta. However, only about 30% of all humans have the correct intestinal flora to produce equol. In these studies, we will test the hypothesis that pathological growth of the prostate gland can be prevented or delayed by dietary equol. We will also determine the cellular mechanisms whereby equol provides such protection. These studies utilize the TRAMP mouse line where spontaneous prostate tumors develop in adult males making this particularly useful for studying the chemopreventive actions of equol. In addition, we will utilize an orthotopic injection model whereby human prostate carcinoma lines that express a luciferase reporter gene are injected into host mice and monitored by in vivo imaging techniques to determine the effects of equol, on growth of prostate tumors. Lastly, we will determine if equol can act by altering the polyamine biosynthetic pathway, thereby inhibiting cell cycle and tumor growth. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most frequently diagnosed cancer in men, and ranks second among cancer-related male deaths in the United States. In this application, we will test the hypothesis that pathological growth of the prostate gland can be prevented or delayed by dietary administration of equol, a product of isoflavone metabolism that has anti-androgenic and estrogen receptor beta activating properties. The long-term goal of this project is to define the mechanism by which equol acts to inhibit the pathological growth of the prostate gland